The Agency’s work
Published on 30/04/2019
Titanium dioxide, Additives, Nanomaterials, REACh (regulation)
Titanium dioxide (TiO2) is used in many industrial and commercial applications (food additives, cosmetics, pigments) and comes in different forms, both micro- and nanometric. ANSES is conducting work to assess the risks associated with the different routes of exposure to TiO2, by ingestion and inhalation. Below is an update on the Agency’s various activities in this domain.
What is titanium dioxide and what is it used for?
Titanium dioxide (TiO2) has different forms, both micro- and nanometric. It is mainly used in powder form, for its ultraviolet-ray absorption properties, but also as a food colouring. TiO2 also has other properties such as chemical resistance, thermal stability and photocatalytic potential.
The annual reporting register for nanomaterials managed by ANSES (R-Nano) documents more than 10,000 tonnes of TiO2 produced or imported into France each year, making it one of the four most commonly produced and imported nanomaterials in France. The register reports a wide range of uses in different sectors such as food, textiles, construction, transport equipment, etc. TiO2 is therefore used in a great variety of finished products such as paints, cosmetics (including sun creams), drugs, toothpastes, food products and construction products (for buildings and public works).
In addition to its size, other physico-chemical properties specific to TiO2 can also vary, and influence its uses and toxicity, such as:
- shape: spherical, elongated, fibrous, etc.;
- modifications of the particle’s surface (coating);
- crystallinity (including three main natural polymorphs: rutile, anatase and brookite).
Titanium dioxide as a food additive
E171 is a food additive in powder form consisting of titanium dioxide particles. It is used in various foods for its colouring (white pigment) and opacifying properties. In France, E171 is used in many food products such as confectionery, pastries and ready-cooked dishes.
The size of its constituent titanium dioxide particles can vary from a few dozen to several hundred nanometres, in dispersed, aggregated or agglomerated form. In addition, the European Food Safety Authority (EFSA), which is responsible for assessing food additives at European level, notes that E171 may contain up to 3.2% nanoparticles per unit weight.
For practical management purposes, Commission Recommendation 2011/696/EU provides a definition of a "nano" product that takes into account both the particle size and the quantity involved; according to this European Commission Recommendation, "‘Nanomaterial’ means a […] material […] where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm".
There are also other regulatory definitions in the INCO and Novel Food Regulations.
Improving knowledge of the effects of TiO2 as a food additive
The use of E171 in food is governed by Regulation (EC) No 1333/2008, and based on a risk assessment carried out by EFSA. Its authorisation for use in food manufacturing must include a mention of "quantum satis" incorporation (i.e. authorised for incorporation in "sufficient quantity", which means that no maximum quantity is specified but that it must be used in accordance with good manufacturing practice, at a level not higher than is necessary to achieve the intended purpose of colouring the food).
As part of its re-evaluation of food colourings, EFSA concluded in 2016 that current consumer exposure to the food uses of E171 was unlikely to pose a health risk. However, it recommended that further studies be carried out to fill gaps in the data on the possible effects of this substance on the reproductive system, which would allow an acceptable daily intake (ADI) to be established.
In addition, in 2017, ANSES produced a specific opinion on an oral toxicity study of E171 (the NANOGUT study conducted by INRA; Bettini et al, 2016). This study showed that chronic oral exposure of rats to the E171 additive could potentially cause precancerous colorectal lesions. In its opinion, the Agency pointed out that although the results presented in the INRA publication did not at this stage call into question EFSA's assessment of E171, the study did demonstrate effects that had not previously been identified, specifically potential promoting effects for carcinogenesis.
The Agency therefore emphasised the need to carry out the studies required for fully characterising the hazard associated with E171, in particular toxicological studies on its carcinogenic potential and reproductive effects.
In a new opinion published in 2019, the Agency reviewed the most recent studies on the oral toxicology of E171 published between 2017 and 2019, and concluded that it had not obtained any new information compared to its 2017 conclusions that would resolve the uncertainties regarding the safety of the additive E171. Pending a better characterisation of the hazard and risks posed by E171, it reiterates its general recommendations on nanomaterials, aimed mainly at limiting the exposure of workers, consumers and the environment, by promoting safe alternatives with equivalent effectiveness.
Carcinogenic effects by inhalation
Because of its physico-chemical properties, exposure to TiO2 by the respiratory route, at a certain level of concentration, may cause lung overload and lead to an inflammatory reaction, responsible for proliferative lesions.
The data currently available, as analysed by ANSES, demonstrate that TiO2 can cause malignant tumours in rats following exposure by inhalation. A sufficient level of evidence means that TiO2 can be considered as a proven carcinogen in animals in light of the experimental data. In humans, the carcinogenic nature continues to be discussed due to the methodological limitations of the available epidemiological studies. These studies are unable to validate or invalidate the animal data.
This information led ANSES, in 2015, to submit a proposal to the European Chemicals Agency (ECHA) to classify TiO2 as a Category 1B carcinogen by inhalation, under Regulation (EC) No 1272/2008 on classification, labelling and packaging of dangerous substances and mixtures (the CLP Regulation), for all its crystalline phases and combinations of particle phases, sizes and morphologies. In 2017, ECHA's Risk Assessment Committee (RAC) concluded that TiO2 in all its forms should be classified as a Category 2 suspected human carcinogen by inhalation. If this proposal is endorsed by the European Commission, industrial companies will be required to apply appropriate labelling to inform workers of the risks faced when handling products containing TiO2.
Furthermore, in order to address the challenges of managing industrial facilities and sites in France, ANSES was asked to define a chronic TRV by inhalation for TiO2-NP (respiratory exposure). Following an in-depth analysis of all the available toxicity data, the Agency is recommending a chronic TRV by inhalation for the P25 form of TiO2-NP of 0.12 µg·m-3. This is also the first TRV developed for a nanomaterial in France.
Other studies under way
Studies funded by the PNR-EST call for projects run by the Agency and describing other potential effects of TiO2 are currently being published. These studies mainly focus on how TiO2 can cross the blood-brain barrier. All the results are expected to be reviewed by EFSA as part of its work to assess food additives.
ANSES is also conducting an assessment of the hazards and risks of TiO2 to human health and the environment under the REACh Regulation. In this context, additional data on the hazards of TiO2 will be required from industry.
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